Process for the preparation of citalopram

ABSTRACT

The present invention provides, inter alia, a novel process for the preparation of Citalopram, a known antidepressant.

CROSS-REFERENCE TO RELATED APPLICATION

The present application claims priority to U.S. Provisional PatentApplication No. 60/324,821, filed Sep. 24, 2001, the teachings of whichare incorporated herein by reference for all purposes.

BACKGROUND OF THE INVENTION

Citalopram is an antidepressant drug that is widely used in both theUnited States and Europe. Its mode of action and activity have beendescribed in various publications. The active ingredient is an HBr oroxalate salt, preferably an HBr salt. Citalopram has the followingstructure:

Several processes have been described in the literature for preparingCitalopram (see, Drugs of Future, 25(6):620 (2000). Citalopram was firstdisclosed in German Patent 2,657,271, which is the German equivalent ofnow expired U.S. Pat. No. 4,136,193. In this patent, 5-bromophthalide(5-BP) was converted via a five-step reaction sequence to Citalopram.This route for preparing Citalopram is depicted in FIG. 1, andconstitutes the basis of several patents and patent applications.

Attempts to reproduce the process described in U.S. Pat. No. 4,136,193for the preparation of Citalopram in the quality specifications requiredfor its use in pharmaceutical applications have been unsuccessful. It isnoted that the quality specifications for pharmaceutical qualityCitalopram are extremely stringent and require material with purity inexcess of 99.7%. Difficulty encountered in manufacturing Citalopram ofthe required purity by the process described in German Patent No.2,657,013, U.S. Pat. No. 4,136,193 and PCT International PublicationNos. WO 00/11926 and WO 00/13648 was recently described by Lundbeck inWO 01/45483 A2 (see, page 2, line 26).

Following is the detailed description of the process described in U.S.Pat. No. 4,136,193. It is noted that the experimental process describedin U.S. Pat. No. 5 4,136,193 is for the 4-chlorophenyl analog, but it isnoted therein that the process is applicable to the 4-fluorophenylderivative as well. As illustrated in FIG. 1, the process described inU.S. Pat. No. 4,136,193 involves a 5-step conversion of 5-bromophthalideto Citalopram.

In the first step, a compound of Formula I (“5-BP”) is reacted withp-fluorophenyl-magnesium halide; in the second step, the intermediate ofa compound of Formula II is isolated and reacted withN,N-dimethylaminopropylmagnesium halide to give the diol of Formula III(“Br-Diol”). The Grignard reaction is conducted in traditional solvents,such as diethyl ether and THF. Unfortunately, the work-up is verycomplex and involves excessive handling of a flammable liquid, i.e.,diethyl ether. The work-up involves the following steps:

-   -   The reaction mixture is quenched into ice water;    -   An aqueous saturated ammonium chloride solution is added;    -   The mixture is extracted with diethyl ether;    -   The ether phase is then extracted with 20% aqueous acetic acid;    -   The acid phase is made alkaline with 10 N aqueous sodium        hydroxide;    -   The aqueous phase is extracted with diethyl ether (2×);    -   The combined ethereal extracts are dried over anhydrous K₂CO₃;    -   The ether extract is treated with activated carbon; and    -   The solvent is evaporated in vacuum to give Br-Diol, an oil.

The above work-up process is very laborious and is not suited forlarge-scale production. Again, it involves the excessive handling offlammable solvents, such as diethyl ether, and it involves numerous unitoperations, thereby reducing productivity. Moreover, it is noted thatBr-Diol is isolated as the free amine and is an oil. The physicalcharacteristics of Br-Diol are important. Since Br-Diol is an oil, itcannot be isolated as a crystalline solid and, thus, it cannot bepurified by techniques such as crystallization/recrystallization.Purification of this oil by crystallization or similar techniques is notdescribed. It is believed that this is one of the major reasons why theprocess described in U.S. Pat. No. 4,136,193 fails to provide Citalopramin the quality, i.e., purity, required for drug applications. Inaddition, in order to meet the tight specifications for Citalopram, itis critical that purity is established at this stage.

In step three, Br-Diol is subjected to a ring closure reaction with 60%aqueous phosphoric acid. In a typical reaction, 5-bromophthalide isheated with excess (30 equivalents) 60% aqueous phosphoric acid for 3 hand then neutralized with saturated aqueous ammonia. The resultingmixture is then extracted with diethyl ether, and the ether extract isdried over potassium carbonate. The ether extract is then treated withactivated charcoal and stripped of solvent under reduced pressure togive the compound of Formula IV (“5-Br”).

As mentioned above, step three employs a large excess of 60% aqueousphosphoric acid. This is troublesome because on reaction completionexcess phosphoric acid has to be neutralized with ammonia.Neutralization is an extremely exothermic process and heat managementbecomes a major issue in the commercial-scale production of thismaterial. In addition, the use of such a large excess of phosphoric acidincreases the cost of commercial scale operations due to the use ofexcess reagents, longer cycle times and reduced loading. Moreover, froma safety point of view, the use of flammable solvents, such as diethylether, is discouraged for the commercial-scale production of organiccompounds.

In step four, 5-Br is reacted with cuprous cyanide in DMF to give, afterthe work-up, Citalopram. The reaction conditions and work-up for theprocess described in U.S. Pat. No. 4,136,193 is as follows:

-   -   5-Br is reacted with CuCN in DMF at reflux for 4 h;    -   The reaction mixture is cooled to 55° C. and quenched into an        aqueous solution of ethylene diamine;    -   The oily layer is separated and the aqueous layer is extracted        with benzene;    -   The combined organic phases are washed with 10% aqueous sodium        cyanide;    -   The organic layer is dried, treated with activated carbon, and        concentrated under vacuum to give an oil;    -   The oil is dissolved in ether and extracted with aqueous acetic        acid;    -   The acetic acid layer is made alkaline with 10 N aqueous sodium        hydroxide and extracted with ether; and    -   The ethereal extract is dried over K₂CO₃, treated with activated        charcoal, and stripped of solvent to give Citalopram.

Unfortunately, there are numerous problems with step four. First, thereaction does not go to completion in 4 h; in reality, conversion after4 h is <10%. Removal 5 of unreacted 5-Br is difficult and normalpurification techniques, such as extraction, crystallization, etc., arenot effective. When the reaction is pushed to achieve higher conversion,formation of numerous unidentified side-products is observed. In short,the process described in U.S. Pat. No. 4,136,193 does not work toprovide acceptable quality Citalopram. Moreover, the work-up islaborious and involves the use of undesirable solvents such as benzeneand diethyl ether.

In the fifth and final step of the process described in U.S. Pat. No.4,136,193, Citalopram is converted to Citalopram-HBr or the oxalate saltin the conventional manner-a process is not described for thisconversion.

Another route for the preparation of Citalopram has been described inU.S. Pat. No. 4,650,884. This process is based on 5-cyanophthalide(“5-CN”). In this process, 5-CN is reacted with 4-fluorophenylmagnesiumhalide and N,N-dimethylaminopropylmagnesium halide to give thecorresponding hydroxy intermediate that is then dehydrated with sulfuricacid to give Citalopram.

Although a number of processes have been described for the preparationof Citalopram, there remains a need in the art for additional processesthat can be prepared in high yield, at the quality specificationsrequired for use in pharmaceutical applications and without thelimitations of the prior art method disclosed in now expired U.S. Pat.No. 4,136,193. Quite surprisingly, the present invention fulfills theseand other needs.

SUMMARY OF THE INVENTION

The present invention provides a novel process for the preparation ofCitaopram and, in particular, Citalopram.HBr. Using the process of thepresent invention, Citalopram.HBr can be readily prepared in highyields, at the quality specifications required for use in pharmaceuticalapplications (i.e., greater than 99.7% pure) and without the limitationsof the prior art methods.

Other features, objects and advantages of the invention and itspreferred embodiments will become apparent from the detailed descriptionwhich follows.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a prior art process used to prepare Citalopram. Thisprocess was originally disclosed in now expired U.S. Pat. No. 4,136,193.

FIG. 2 illustrates a process in accordance with one aspect of thepresent invention that can be used to prepare Citalopram in high yieldand at the quality specifications required for use in pharmaceuticalapplications.

FIG. 3 illustrates an example of a feed composition to be purified.

FIGS. 4 illustrates that the product contained in the extract, i.e., therecovered extract, does not contain any detectable amounts of 5-Br.

FIG. 5 illustrates the recovered raffinate.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

The present invention provides a process for the preparation ofCitalopram and, in particular, Citalopram.HBr. FIG. 2 illustrates anexemplary process for the preparation of Citalopram.HBr in accordancewith the present invention.

As illustrated in FIG. 1, the present invention provides a salt of thecompound of Formula III, which can be isolated as a crystallinematerial, and a novel, simplified process for preparing such salt. Theability to isolate a salt of the compound of Formula III allows one toset the purity at this step by allowing one to get rid of impuritiesthat would otherwise be carried through the process, making itimpossible to prepare high quality Citalopram.

As such, in one embodiment, the present invention provides a crystallinesalt of the compound of Formula III having the following structure:

In a presently preferred embodiment, the crystalline salt is an acidsalt. Suitable acid salts include, but are not limited to, a HCl salt, aHBr salt, a H₂SO₄ salt, a H₃PO₄ salt, a methanesulfonic acid salt, atrifluoroacetic acid salt, an acetic acid salt, a fumaric acid salt anda citric acid salt. In a presently preferred embodiment, the crystallinesalt is an HCl salt having the following structure:

In another aspect, the present invention provides a method for preparingthe salt of the compound of Formula III, the process comprising: (a)contacting a compound of Formula I having the following structure:

with 4-fluorophenyl magnesium bromide to form an intermediate of FormulaII having the following structure:

(b) contacting the intermediate of Formula II with dimethylaminopropylmagnesium chloride in an organic solvent to form a reaction mixture; and(c) quenching the reaction mixture with an acid to form a productmixture comprising the salt of the compound of Formula III. In oneembodiment of the above process, the crystalline salt is an acid salt.Suitable acid salts include, but are not limited to, a HCl salt, a HBrsalt, a H₂SO₄ salt, a H₃PO₄ salt, a methanesulfonic acid salt, atrifluoroacetic acid salt, an acetic acid salt, a fumaric acid salt anda citric acid salt. In a presently preferred embodiment, the crystallinesalt is an HCl salt having the following structure:

In connection with this particular embodiment, it has been surprisinglyfound that depending on the isolation and recrystallization proceduresused to isolate the HCl salt of the compound of Formula III, differentpolymorphs are obtained. For instance, the crude HCl salt of thecompound of Formula III, isolated from a mixture of THF/toluene/aqueousHCl has one melting point, whereas the crude HCl salt of the compound ofFormula III recrystallized from butanol has a second melting point.

As such, in one embodiment, the acid used in step (c) is a memberselected from the group consisting of HCl, HBr, H₂SO₄, H₃PO₄,methanesulfonic acid, trifluoroacetic acid, acetic acid, fumaric acidand citric acid. Again, in a preferred embodiment, the acid is aqueousHCl.

In one embodiment, the solvent used in step (b) is an organic solvent.

Suitable organic solvents include, but are not limited to, diethylether,t-butylmethylether, THF, dioxane, toluene, xylene and mixtures thereof.In a preferred embodiment, the organic solvent used in step (b) is amixture of THF and toluene.

In a preferred embodiment, the above method further comprises: (d)isolating the salt of the compound of Formula III from the productmixture. In one embodiment, step (d) comprises: (i) filtering theproduct mixture to obtain the salt of the compound of Formula III. Inanother embodiment, step (d) further comprises: (ii) washing the salt ofthe compound of Formula III with water and toluene. In yet anotherembodiment, step (d) further comprises: (iii) recrystallizing the saltof the compound of Formula III from a member selected from the groupconsisting of 1-butanol, 2-butanol and water. In a preferred embodiment,the salt of the compound of Formula III is recrystallized from2-butanol.

In another aspect, the present invention provides a method for preparinga compound of Formula IV having the following structure:

the method comprising: (a) contacting a salt of the compound of FormulaIII having the following structure:

with about 2 to about 10 equivalents of phosphoric acid to form areaction mixture; (b) adding an organic solvent to said reactionmixture; and (c) quenching said reaction mixture with base to form aproduct mixture comprising said compound of Formula IV.

With respect to this method, the patent literature (e.g., U.S. Pat. No.4,136,193) teaches that an excess of 60% phosphoric acid (˜30equivalents) is required in order to achieve ring closure. However, ithas now been surprisingly found that ring closure can be achieved withsignificantly fewer equivalents of phosphoric acid (e.g., about 2 toabout 10 equivalents). This finding gives rise to a purer product andnumerous other advantages. For instance, one of the problems associatedwith the process disclosed in U.S. Pat. No. 4,136,193 for makingCitalopram is neutralization of excess phosphoric acid with ammonia. Asexpected, this reaction is very exothermic and takes a long time toneutralize the reaction mixture. Long neutralization time equates tolonger cycle time, which in turn means lower productivity. Since fewerequivalents of phosphoric acid are used and the amount of ammonia neededto quench the excess phosphoric acid is reduced, the overall batch sizeis higher than the normal batch size by nearly 20%. As such, the methodof the present invention provides purer product, is more suited forcommercial scale production, and has much higher productivity.

In one embodiment, the salt of the compound of Formula III is a HClsalt. In another embodiment, the phosphoric acid is about 20% to about60% phosphoric acid. In a preferred embodiment, the compound of FormulaIII is contacted with about 6 to about 9 equivalents of 20% phosphoricacid. In another preferred embodiment, the compound of Formula III iscontacted with about 9 equivalents of 20% phosphoric acid. It will bereadily apparent to those of skill in the art that other acids can beused in place of phosphoric acid. Suitable acids include, but are notlimited to, HCl, HBr, sulfuric acid, trifluoroacetic acid,and methanesulfonic acid, etc.

In another embodiment, the organic solvent in step (b) is a memberselected from the group consisting of toluene, benzene, xylene,diethylether, t-butylmethylether, dioxane, and mixtures thereof. In apreferred embodiment, the organic solvent in step (b) is toluene.

In another embodiment, the base is a member selected from the groupconsisting of ammonium hydroxide, sodium hydroxide and potassiumhydroxide. In a presently preferred embodiment, the base is aqueousammonium hydroxide.

In a preferred embodiment, the above method further comprises: (c)isolating the compound of Formula IV from the product mixture. In oneembodiment, step (c) comprises: (i) separating the organic phase and theaqueous phase; (ii) re-extracting the aqueous phase with toluene; (iii)combining the organic phases to form a combined organic phase andwashing the combined organic phase with water; and (iv) distilling thewashed organic phase to obtain the compound of Formula IV.

In a preferred embodiment, the above method is carried out at atemperature of about 80° C.±10° C.

In another aspect, the present invention provides a method for preparinga compound of Formula V having the following structure:

the method comprising: (a) contacting a compound of Formula IV havingthe following structure:

with a mixture of cuprous cyanide and sodium cyanide to form a reactionmixture; (b) heating the reaction mixture until the reaction iscomplete; and (c) quenching the reaction mixture to form a productmixture comprising the compound of Formula V. It has been found that amixture of cyanating agents works surprisingly well for carrying outthis method.

In one embodiment, the compound of Formula IV is in a first organicsolvent. Suitable first organic solvents include, but are not limitedto, toluene, benzene, xylene, diethylether, t-butylmethylether, dioxane,and mixtures thereof. In a preferred embodiment, the first organicsolvent is toluene. In another embodiment, the mixture of cuprouscyanide and sodium cyanide is in a second organic solvent. Suitablesecond organic solvents include, but are not limited to,N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidione,quinoline, collidine, xylene, dimethylsulfone, hexamethylphosphoramideand trifluoromethylchlorobenzene. In a preferred embodiment, the secondorganic solvent is N,N-dimethylformamide.

It will be readily apparent to those of skill in the art that the ratioof cuprous cyanide:sodium cyanide in the mixture of cuprous cyanide andsodium cyanide can be varied. In a presently preferred embodiment, theratio of cuprous cyanide:sodium cyanide in the mixture of cuprouscyanide and sodium cyanide is about 2.5:1.0 to about 1:2.5. In apresently preferred embodiment, the ratio of cuprous cyanide:sodiumcyanide in the mixture of cuprous cyanide and sodium cyanide is about0.50:1.0 to about 2.5:1. In another preferred embodiment, the ratio ofcuprous cyanide:sodium cyanide in the mixture of cuprous cyanide andsodium cyanide is about 0.75:1.0 to about 1.0:1.0. It will be readilyapparent to those of skill in the art that other mixtures of cyanatingagents (e.g., KCN:CuCN or Metal-CN:CuCN complexes) can be used in theabove method of the present invention.

In one embodiment, the first organic solvent is removed from thereaction mixture prior to step (b). In another embodiment, the reactionmixture is quenched with a member selected from the group consisting ofaqueous sodium cyanide and aqueous potassium cyanide. In a preferredembodiment, the reaction mixture is quenched with 10% aqueous sodiumcyanide.

In a preferred embodiment, the above method further comprises: (d)isolating the compound of Formula V from the product mixture. In oneembodiment, step (d) comprises: (i) adding ethylenediamine and a firstorganic solvent to the reaction mixture and separating the organic phaseand the aqueous phase; (ii) re-extracting the aqueous phase with thefirst organic solvent; (iii) combining the organic phases to form acombined organic phase and back-extracting the combined organic phasewith an acid to form an acid extract; (iv) neutralizing the acid extractwith a base to a pH of about 8.5 to about 11 to form a neutralizedextract; (v) extracting the neutralized extract with a second organicsolvent to form a second organic solvent extract; (vi) treating thesecond organic solvent extract with charcoal and removing the secondorganic solvent to generate the compound of Formula V.

In a preferred embodiment of step (d), the first and second organicsolvents are independently selected from the group consisting oftoluene, benzene, xylene, diethylether, t-butylmethylether, dioxane, andmixtures thereof. In another preferred embodiment, the first and secondorganic solvents are both toluene.

In one embodiment, the acid in step (iii) is a member selected from thegroup consisting of HCl, HBr, H₂SO₄, H₃PO₄, trifluoroacetic acid andacetic acid. In a preferred embodiment, the acid in step (iii) is 20%aqueous acetic acid. In one embodiment, the base in step (iv) is amember selected from the group consisting of sodium hydroxide, potassiumhydroxide and sodium carbonate. In a preferred embodiment, the base instep (iv) is sodium hydroxide. In one embodiment, the acid extract instep (iv) is neutralized with the base to a pH of about 9 to about 10.

In another aspect, the above method further comprises purifying thecompound of Formula V using simulated moving bed (SMB) chromatographyhaving a stationary phase and a mobile phase. It has been found that SMBchromatography works surprisingly well for removing non-polar impuritiesfound in the reaction mixture. In one embodiment, the stationary phaseis a reverse phase silica gel and the mobile phase is an organicsolvent/water mixture. A C18-derivatized silica gel is an example of asuitable reverse phase silica gel. Typically, the pH of the mobile phaseis about 1.5 to about 4.0, more preferably about 2.5. The pH of themobile phase can be maintained by, for example, the addition of 0.1 to2% trifluoroacetic acid. In a preferred embodiment, the organic solventin the mobile phase is methanol. In another preferred embodiment, theorganic solvent in the mobile phase is ethanol. In another preferredembodiment, the organic solvent in the mobile phase is acetonitrile.

In another embodiment, the stationary phase is a normal phase silica geland the mobile phase is an organic solvent mixture. In one embodiment,the organic solvent mixture is a mixture of an alcohol, a hydrocarbonand an organic base. Suitable alcohols include, but are not limited to,methanol, ethanol, n-propanol and isopropanol. Suitable hydrocarbonsinclude, but are not limited to, heptane, n-heptane, hexane, isohexane,toluene, cyclohexane, benzene and combinations thereof. Suitable organicbases include, but are not limited to, triethylamine, diethylamine,trimetylamine, dimethylamine, tripropylamine, tributylamine,diisopropylethylamine, dicyclohexylamine and diethylisopropylamine. In apreferred embodiment, the organic base is present in the organic solventmixture at about 0.05 to about 5%, more preferably at about 0.1 to about0.5% and, even more preferably, at about 0.2 to about 0.4%. In apreferred embodiment, the organic solvent mixture is a mixture ofethanol, heptane and triethylamine.

In another embodiment, the stationary phase is a chiral phase silica geland the mobile phase is an organic solvent mixture. Suitable chiralphase silica gel stationary phases include, but are not limited to,CHIRALPAK® AD™; CHIRALPAK® AS™; CHIRALCEL® OD™; and CHIRALCEL® OJ™, allof which are commercially available from Daicel, through its subsidiary,Chiral Technologies Inc. In one embodiment, the organic solvent mixtureis a mixture of an alcohol (which may or may not be denatured with, forexample, a hydrocarbon such as n-heptane), a hydrocarbon and an organicbase. Suitable alcohols include, but are not limited to, methanol,ethanol, n-propanol and isopropanol. Suitable hydrocarbons include, butare not limited to, heptane, n-heptane, hexane, isohexane, toluene,cyclohexane, benzene and combinations thereof. Suitable organic basesinclude, but are not limited to, triethylamine, diethylamine,trimetylamine, dimethylamine, tripropylamine, tributylamine,diisopropylethylamine, dicyclohexylamine and diethylisopropylamine. In apreferred embodiment, the organic base is present in the organic solventmixture at about 0.05 to about 5%, more preferably at about 0.1 to about0.5% and, even more preferably, at about 0.2 to about 0.4%. In apreferred embodiment, the organic solvent mixture is a mixture ofethanol, heptane and triethylamine.

In another embodiment, the compound of Formula V is further purifiedusing single column chromatography having a stationary phase and amobile phase. It has been found that single column chromatography workssurprisingly well for removing any non-polar impurities found in thereaction mixture. Suitable stationary and mobile phases are similar tothose described above in connection with the SMB chromatography.

In another aspect, the present invention provides a method for preparinga compound of Formula VI having the following structure:

the method comprising: (a) dissolving a compound of Formula V having thefollowing structure:

in an organic solvent to form a reaction mixture; and (b) contacting thereaction mixture with HBr to form a product mixture comprising thecompound of Formula VI.

In one embodiment, the organic solvent in step (a) is a member selectedfrom the group consisting of acetone, methylethylketone, ethylacetate,toluene, benzene, xylene, diethylether, t-butylmethylether, dioxane, andmixtures thereof. In a preferred embodiment, the organic solvent in step(a) is diethylether. In another preferred embodiment, the organicsolvent in step (a) is acetone.

In one embodiment, the HBr is gaseous HBr. In an example of thisembodiment, the method comprises bubbling gaseous HBr into the reactionmixture to form a product mixture comprising the compound of Formula VI.In another embodiment, the HBr is aqueous HBr and the reaction mixtureis contacted with aqueous HBr to form a product mixture comprising thecompound of Formula VI.

In a preferred embodiment, the above method further comprises: (c)isolating the compound of Formula VI from the product mixture. In oneembodiment, step (c) comprises: (i) cooling the product mixture andfiltering the product mixture to obtain the compound of Formula VI as aprecipitated solid; (ii) washing the precipitated solid with an organicsolvent; and (iii) drying the precipitated solid to obtain the compoundof Formula VI. In one embodiment, step (c) further comprises: (iv)recrystallizing the compound of Formula VI. In one embodiment, thecompound of Formula VI is recrystallized from a solvent mixture oftoluene and methanol. In another embodiment, the compound of Formula VIis recrystallized from a solvent mixture of methanol andisopropylalcohol (IPA).

In another embodiment, step (iv) comprises: (i′) combining theprecipitated solid with toluene and methanol to form a mixture andheating the mixture; (ii′) filtering the mixture through Celite andslowly cooling the mixture; and (iii′) filtering the mixture to obtainthe crystallized solid, washing the crystallized solid with toluene, anddrying the crystallized solid to obtain the compound of Formula VI. Inone embodiment, in step (ii′), the mixture is cooled to about ambienttemperature. In another embodiment, in step (ii′), the mixture is cooledto about 0° C. to about 5° C.

In yet another embodiment, step (iv) comprises: (i′) combining theprecipitated solid with methanol and isopropylalcohol (IPA) to form amixture and heating the mixture; (ii′) filtering the mixture throughCelite and slowly cooling the mixture; and (iii′) filtering the mixtureto obtain the crystallized solid, washing the crystallized solid withisopropylalcohol, and drying the crystallized solid to obtain thecompound of Formula VI. In one embodiment, in step (ii′), the mixture iscooled to about ambient temperature. In another embodiment, in step(ii′), the mixture is cooled to about 0° C. to about 5° C.

In another embodiment, the present invention provides a process for theremoval of demethyl- (A) and didemethyl- (B) impurities from crudeCitalopram mixtures, wherein the demethyl- and didemethyl-impuritieshave the following structures:

Demethyl- (A) and didemethyl- (B) impurities are common impuritiesformed at various stages during the preparation of Citalopram.Unfortunately, these troublesome impurities present a challenge inremoval due to their structural proximity to Citalopram.

As such, the present invention provides a method for removing demethyl-and didemethyl-impurities from a crude Citalopram mixture containingdemethyl- and didemethyl-impurities in a solvent, the method comprising:(a) contacting the mixture of Citalopram with a scavenger resin having afunctional group that is reactive with a primary or secondary amine toform resin-bound demethyl- and/or didemethyl-impurities, wherein thescavenger resin is insoluble in the solvent; and (b) filtering theresin-bound demethyl- and/or didemethyl-impurities, thereby removing thedemethyl and/or didemethyl-impurities from the mixture of Citalopram.

In one embodiment of the above method, the functional group on thescavenger resin includes, but is not limited to, isocyanates,isothiocyanates, acid chlorides, esters and anhydrides. In someembodiment, the scavenger resin can have more than one functional groupand, in this case, the functional groups can be the same or different.It has been found that such functional groups react with the primaryand/or secondary amine functionalities present in impurities A and B,virtually in an irreversible fashion, thereby attaching impurities A andB to the scavenger resin. The attachment of impurities A and B to thescavenger resin renders such impurities insoluble as well.

The scavenger resin can be any resin that (1) is insoluble in thesolvent in which the product is dissolved; (2) is non-reactive with thesolvent in which the product is dissolved; and (3) contains a functionalgroup that is reactive with a primary and/or a secondary amine. In oneembodiment, the scavenger resin is a polystyrene-based resin. In anotherembodiment, the scavenger resin is a silica gel-based resin. In apreferred embodiment, the scavenger resin is a polystyrene-based resinhaving the following structure:

wherein: R is a functional group that is reactive with a primary and/orsecondary amine such as those described above.

The above method is typically carried out by stirring a crude Citaloprammixture containing A and/or B in an appropriate solvent with a scavengerresin having a functional group that is reactive with the primary and/orseconday amine functionalities present in A and B, respectively.Suitable solvents include, but are not limited to, toluene, benzene,xylene, diethylether, t-butylmethylether, dioxane, and mixtures thereof.The resulting mixture is a heterogeneous mixture as the scavenger resinis also insoluble in the solvent. It is thought that impurities A and B,but not Citalopram, attach to the resin by making a covalent bondbetween a primary or secondary amine functionality and the functionalgroup on the scavenger resin, thereby rendering them insoluble. A simplefiltration of the resin-bound, i.e., insoluble, impurities A and Baffords a purified Citalbpram solution virtually free of impurities Aand B.

The above method has a number of significant advantages including, butnot limited to, the following: (1) it selectively renders otherwisesoluble impurities A and B insoluble by binding them to the insolubleresin through the reaction of the reactive end groups of the scavengerresin and the primary and secondary amine functionalities present inimpurities A and B; (2) the scavenger resin will bind any other impuritycontaining a primary or secondary amine functionalities and render theminsoluble as well; (3) the scavenger resin cannot react with the desiredCitalopram, which has a tertiary amine functionality; (4) once the resinbinds to the impurities A, B (or any other impurity containing a primaryor secondary amine functionality) rendering them insoluble, only asimple filtration is required to remove these impurities, therebyminimizing any loss (i.e., any loss due to the acid/base wash and/orcrystallization and recrystallization utilized in the method disclosedin PCT Patent Publication No. WO 01/45483 A2); and (5) once thefiltration is performed, a purified Citalopram solution is obtained andthe purified Citalopram can be recovered by a simple evaporation of thesolvent.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results.

EXAMPLES

A. Preparation of Dimethylaminopropyl Magnesium Chloride

-   -   A 30% aqueous sodium hydroxide (1.04 kg, 7.80 mol, 1.10 eq.)        solution was added to a mixture of 65% aqueous        dimethylaminopropyl chloride hydrochloride (1.71 kg, 7.04 mol,        1.00 eq.) and toluene (0.167 kg) at <20° C.    -   The phases were separated.    -   The organic phase was combined with THF (0.600 kg) and dried        over molecular sieves (Siliporite NK10, 0.227 kg).    -   Approximately 5% of the dried dimethylaminopropyl chloride        solution was added to a mixture of magnesium (0.170 kg, 7.00        mol, 1.00 eq.), ethyl bromide (0.0038 kg, 0.035 mol, 0.0050        eq.), and THF (1.60 kg).    -   The resulting mixture was heated to reflux (>68° C.) and the        remaining dimethylaminopropyl chloride solution was added over        1.5 h.    -   Reflux (>68° C.) was maintained throughout the addition period        by adjusting the addition rate and heating and/or cooling as        necessary.    -   The mixture was refluxed (>70° C.) for 1 h, then cooled to        ambient temperature and stored under a dry nitrogen atmosphere.

B. Preparation of(4-Bromo-2-hydroxymethyl)phenyl-(4-fluorophenyl)-(3-dimethylaminopropyl)methanol hydrochloride

-   -   A solution of 1.1 M 4-fluorophenyl magnesium bromide in THF        (5.57 kg, 6.01 mol, 1.28 eq.) was added to a mixture of        5-bromophthalide (1.00 kg, 4.69 mol, 1.00 eq), and toluene (6.25        kg) at <20° C. over 1 h.    -   The mixture was stirred at <20° C. for 0.5 h.    -   A solution of 1.8 M dimethylaminopropyl magnesium chloride (3.90        kg, 7.02 mol, 1.50 eq.) was added to the mixture over 2 h,        maintaining <30° C. with cooling.    -   The resulting mixture was stirred ambient temperature for 16 h.    -   The mixture was quenched into 6.23% aqueous hydrochloric acid        (9.9 kg, 19.3 mol, 4.1 eq.).    -   The slurry was stirred at ambient temperature for 1 h and        filtered.    -   The product was then washed with water (2.00 kg) and toluene        (4.00 kg).    -   The off-white solids were dried at 35-40° C. under vacuum to        yield 1.63 kg (80.4% yield) of crude bromodiol*HCl.

C. Purification of Bromodiol HCl

-   -   A mixture of crude bromodiol*HCl (1.60 kg) and 2-butanol (8.00        kg) was heated to 70° C. to form a hazy solution and filtered        through a bed of celite.    -   The resulting solution was cooled slowly to 5° C. to precipitate        the product.    -   The resulting slurry was filtered and washed with 2-butanol        (1.60 kg).    -   The off-white solids were dried at 35-40° C. under vacuum to        yield 1.18 kg (73.8% recovery from crude) of bromodiol*HCl.

The properties of the Bromodiol*HCl are as follows:

-   -   HPLC area % purity: 99.9%    -   mp (DSC): 183° C.    -   ¹H NMR (d-DMSO): δ10.19 (s, 1H), δ7.0-7.8 (m, 7H), δ5.90 (s,        1H), δ5.17 (s, 1H), δ4.49 (d, 1H), δ3.97 (d, 1H), δ3.02 (m, 2H),        δ2.65 (s, 6H), δ2.21 (m, 2H), δ1.65 (m, 1H), δ1.36 (m, 1H).

D. Preparation of5-Bromo-1-(4-fluorophenyl)-1-(3-dimethylaminopropyl)-phthalan (“5-Br”)

-   -   A mixture of bromodiol*HCl (1.12 kg, 2.59 mol, 1.00 eq.) and 60%        phosphoric acid (12.7 kg, 77.8 mol, 30.0 eq.) was heated to        90° C. for 1 h.    -   The mixture was cooled to <10° C.    -   Toluene (6.72 kg) and water (8.96 kg) were added to the solution        and the mixture was quenched with 28% aqueous ammonium hydroxide        (9.37 kg, 74.9 mol, 28.9 eq.), maintaining <25° C.    -   The phases were separated and the aqueous layer was re-extracted        with toluene (4.48 kg).    -   The organic phases were combined and washed with water (4.0 kg).    -   The solvent was distilled from the washed organic extracts to        yield 977 g (99.2% yield, 95.2% yield corrected for residual        solvents) of 5-Br as an orange oil.

The properties of 5-Br are as follows:

-   -   HPLC area % purity: 99.0%    -   ¹H NMR (d-DMSO): δ7.1-7.6 (m, 7H), δ5.10 (m, 2H), δ2.51 (m, 2H),        δ2.11 (m, 2H), δ2.01 (s, 6H), δ1.23 (m, 2H).

E. Modified Process for the Preparation of 5-Br

-   -   A mixture of bromodiol*HCl (0.200 kg, 0.462 mol, 1.00 eq.) and        20% phosphoric acid (2.04 kg, 4.16 mol, 9.00 eq.) was heated to        90° C. for 2.5 h.    -   The mixture was cooled to <10° C.    -   Toluene (1.20 kg) was added to the solution and the mixture was        quenched with 28 % aqueous ammonium hydroxide (0.574 kg, 4.59        mol, 9.93 eq.), maintaining <25° C.    -   The phases were separated and the aqueous layer was re-extracted        with toluene (0.800 kg).    -   The organic phases were combined and washed with water (0.800        kg).    -   The solvent was distilled from the washed organic extracts to        yield 164 g (93.6% yield) of 5-Br as an orange oil.

The properties of 5-Br are as follows:

-   -   HPLC area % purity: 99.2%    -   ¹H NMR (d-DMSO): δ7.1-7.6 (m, 7H), δ5.10 (m, 2H), δ2.51 (m, 2H),        δ2.11 (m, 2H), δ2.01 (s, 6H), δ1.23 (m, 2H).

F. Process for the Preparation of5-Cyano-1-(3-dimethylaminopropyl)-1-(p-fluorophenyl)phthalane(“Citalopram” or “5-CN“)

-   -   A solution of        5-bromo-1-(3-dimethylaminopropyl)1-(p-fluorophenyl)phthalane        (100.5 g, 0.266 mol) in toluene was added to a mixture of        cuprous cyanide (50.0 g, 0.558 mol) and sodium cyanide (9.8 g,        0.200 mol) in of N,N-dimethylformamide (450 mL)    -   Toluene was removed by distillation and the resulting mixture        was heated to 154-159° C. under nitrogen until the desired        conversion was achieved.    -   The reaction mixture was then chilled to 60-70° C. and quenched        with a 10% aqueous NaCN solution (350 g).    -   Aqueous ethylenediamine (41% solution, 140 g) and toluene (500        mL) were added and the mixture was filtered.    -   The organic layer was separated and the aqueous layer was        extracted with toluene (2×100 mL).    -   The combined organic extracts were washed with water (2×100 mL).    -   The organic extract was then extracted with 20% acetic acid        solution (2×250 mL).    -   The combined acetic acid extracts were neutralized with 16.6%        aqueous NaOH to a pH of about 9 to about 10 and extracted with        toluene (3×300 mL).    -   The combined toluene extracts were treated with activated        charcoal (16.1 g) and stripped of solvent under reduced pressure        to give crude Citalopram (72.3 g, 84%) as a light brown oil.

The properties of 5-CN are as follows:

-   -   HPLC purity: 95% with 5% unreacted 5-Br    -   ¹H NMR (DMSO-d₆): δ 7.6 (s, 1H, 4-H aromatic proton), 6.98 to        7.52 (m, 6H, aromatic protons), 5.25 (d, 1H, 3-H_(a)), 5.15 (d,        1H, 3-H_(b)), 3.08 (t, 2H, 3′-CH₂), 2.71 (s, 6H, —N(CH₃)₂), 2.49        to 2.27 (m, 2H, 1′-CH₂), 1.82 to 1.71 (m, 2H, 2′-CH₂);    -   LC/MS: m/z, 325 (M+1).

G. Process for the Purification of Crude 5-CN

The crude 5-CN product is dissolved in a mixture of heptane/ethanol/TEA(90%: 10%:0.1%), and separated using Multi-Column Chromatography (MCC)equipment (SMB) to provide 5-CN with <0.1% 5-Br. The mobile phase isheptane/ethanol/TFA. The stationary phase is CHIRALCEL OD™. MCCseparation has been demonstrated on 400 g scale and the product isolatedfrom the separation was >99.9% pure. The product was so pure that whenit was converted to the HBr salt, it maintained its purity and did notrequire additional purification—a 20% savings in the yield.

H. Process for the Preparation of5-Cyano-1-(3-dimethylaminopropyl)-1-(p-fluorophenyl)phthalane HBr(Citalopram-HBr)

-   -   HBr gas (18.0 g, 0.223 mol) was bubbled into a stirred solution        of pure 5-CN (72.3 g, 0.223 mol) in 723 mL acetone at 20-25° C.    -   The resulting slurry was cooled to 0-5° C. and filtered.    -   The product was washed with cold acetone (3×100 mL) and dried in        vacuo (60-80° C. at 5-10 mmHg) to give Citalopram-HBr (69.8 g,        77.3%), a white solid.

L Purification of Citalopram-HBr

-   -   A mixture of the crude product (69.8 g), toluene (1117 g), and        methanol (138 g) was heated to 60-70° C.    -   The resulting solution was filtered through celite and slowly        cooled to ambient temperature.    -   The crystallized solid was filtered, washed with 100 mL toluene,        and dried in vacuo (60-80° C. at 10 mmHg) to give pure        Citalopram-HBr (53.2 g, 76.2%), a white solid.

The properties of Citalopram-HBr are as follows:

-   -   mp (DSC): 186° C.    -   HPLC Purity: 99.8%    -   IR (KBr): 2931, 2655, 2229,1507, 1217, 1028, 1013, 835 cm⁻¹;    -   ¹H NMR (DMSO-d₆): δ 9.15 (s, 1H, —NH(CH₃)₂), 7.71 to 7.91 (m,        3H, aromatic protons), 7.52 to 7.64 (m, 2H, aromatic protons),        7.06 to 7.27 (m, 2H, aromatic protons), 5.08 to 5.28 (q, 2H,        3-H), 3.3 (t, 2H, 3′-CH₂), 2.65 (s, 6H, —NH(CH₃)₂), 2.2 (t, 2H,        1′-CH₂), 1.29 to 1.60 (m, 2H, 2′-CH₂).

J. Process for the Preparation of5-Cyano-1-(3-dimethylaminopropyl)-1-(p-fluorophenyl)phthalane HBr(Citalopram-HBr)

In addition to the foregoing method, Citalopram-HBr can be preparedusing aqueous HBr. It has been found that the resulting product preparedusing aqueous HBr is equivalent to that prepared using gaseous HBr inboth yield and purity.

C.HBr Salt Formation

-   -   48% HBr (aq) (54.1 g, 0.321 mol) is added to a stirred solution        of 5-CN (104.1 g, 0.31 mol) in Toluene (366 g) at 5-10° C.    -   The resulting slurry is cooled to 0-5° C. and filtered.    -   The product is washed with cold Toluene (2×107 mL) and dried in        vacuo (60-80° C. at 5-10 mm Hg) to afford C-HBr (97.5 g, 93.6%)        as a white solid.

Recrystallization/Purification

A recrystallization is not necessary when using 5-CN purified by SMBchromatography. However, the following can be performed if furtherpurification is required or desired.

-   -   A mixture of C-HBr (97.5 g, 0.301 mol), methanol (103.6 g) and        isopropanol (207.2 g) is heated to 60-70° C.    -   The resulting solution was cooled to 0° C. and filtered.    -   The recrystallized product was washed with cold isopropanol        (2×75 mL) and dried in vacuo (60-80° C. at 5-10 mm Hg) to afford        C-HBr (88.6 g, 85.1%) as a white solid.

The properties/characterization of pure C-HBr are as follows:

-   -   mp (DSC): 187° C.    -   HPLC Purity: 99.8%    -   5-Br: None detected    -   Total Impurities: ≦0.2%    -   Unknown Inpurities ≦0.1%: None detected    -   IR(KBr): 2931, 2655, 2229, 1507, 1217, 1028, 1013, 835 cm⁻¹;    -   ¹H NMR (DMSO-d₆): δ 9.15 (s, 1H, —NH(CH₃)₂), 7.71 to 7.91 (m,        3H, aromatic protons), 7.52 to 7.64 (m, 2H, aromatic protons),        7.06 to 7.27 (m, 2H, aromatic protons), 5.08 to 5.28 (q, 2H,        3-H), 3.3 (t, 2H, 3′-CH₂), 2.65 (s, 6H, —NH(CH₃)₂), 2.2 (t, 2H,        1′-CH₂), 1.29 to 1.60 (m, 2H, 2′-CH₂).

K. Removal of Demethyl and Didemethyl Impurites from a Crude CitalopramMixture

-   -   Methylisocyanate polystyrene resin (0.34 g, 0.18 mol isocyanate)        is added to a solution of 5-CN (0.92 g) in Toluene (10 g) and        stirred at room temperature.    -   After 2 h at room temperature, the resin was filtered and        Toluene was evaporated in vacuo (50-60° C. at 5-10 mm Hg) to        afford product with 70% less demethyl impurity (A).

L SMB Purification of Citalopram-HBr

Experimental

The feed mixture is an oil recovered from the cyanation step andcontains several impurities (polar and non-polar). These impurities canmostly be removed by standard reworking of the product (e.g., bycrystallization and solvent exchange). However, one impurity is notremoved by these techniques. This impurity is the starting material ofthe previous step. It is the 5-Br intermediate that is converted intoCitalopram during the cyanation step.

The separation of a mixture of Citalopram and 5-Br intermediate in theproportion 95/5 (HPLC area % at 232-nm) was examined by chromatographyand more specifically by the simulated moving bed technique. FIG. 3(reverse phase analysis) gives an example of the feed composition. Thelargest peak is the Citalopram peak. The second largest peak is the 5-Brintermediate. The other peaks are of lesser interest for thechromatographic separation.

The following equipment was used for the experiment. SMB unit: Licoseplaboratory unit from NOVASEP (Brabois (54), France) equipped with 8axial compression columns from MERCK (Darmstadt, Germany). Each columnwas 50-mm internal diameter and was prepared using 110-g of CHIRALCELOD™ 20-μm chiral stationary phase (Chiral Technologies Inc, Exton, USA).The average column length was 10.3-cm. The mobile phase used for theseparation was a mixture of ethanol (denatured with n-heptane) andn-heptane in the proportion 10/90 % (v/v.). Triethylamine was added as amodifier (0.2% total volume). The separation was conducted at 30° C.Under such conditions, the compound of interest (Citalopram) is thesecond eluting compound and will be designed as the Extract, 5-Br willbe the Raffinate.

Each column was individually tested with a diluted solution of themixture to be separated (14.2-g/1). The injected volume was 0.5-ml.Detection was performed at 254-nm and the flow rate was 100-ml/min. The5-Br average elution time is 1.92-min while the Citalopram has anaveraged elution time of 3.10-min. The average to (or dead volume) ofthe column was 1.51-min. The average retention factor for the 5-Br was0.27 and was 1.04 for the Citalopram. The average selectivity of theseparation was 3.84.

Separation Parameters

The separation was conducted using 703.1 g of a mixture of Citalopramand 5-Br prepared according to the cyanation procedure. The feedcomposition is 95% of Citalopram and 5% of 5-Br (area % by HPLC at232-nm). The feed contains other impurities, but they were not takeninto account in the calculation of the feed composition. The feedconcentration for this step was 22.7-g/l.

The set of parameters used for the separation was: Zone I Period Eluent(recycle) Extract Zone II Feed Zone III Raffinate Zone IV min ml/minml/min ml/min ml/min ml/min ml/min ml/min ml/min 1.65 86.7 190 76.7113.3 40 @ 153.3 50 103.3 22.7 g/lProduct Recovery

Each recovered fraction (extract and raffinate) was evaporated in 20-Lrotary evaporators (Genser, Germany). The Extract fraction wasevaporated to dryness and the product was recovered as a crystal. Theevaporation step was conducted at 40° C. (waster bath) and under vacuum(1 50-mbar to start the process and down to 80-mbar for drying theproduct) with 50-rpm for the flask speed.

The solvent recovered was sampled and tested and acceptable low amountof product was detected (traces).

The raffinate was re-dissolved in a small amount of ethanol denaturedand evaporated in a 1-L flask using the laboratory evaporator (Buchii).The raffinate product (5-Br) was recovered as a viscous oil.

A sample of each recovered fraction was analyzed using a C₁₈ column(reverse phase) and a gradient of water with TFA (trifluoroaceticacid)and acetonitrile with TFA.

Separation Performance

The total quantity of product recovered is 675.3-g (all fractionsincluded), which gives an overall yield for the process of 96%. The 4%loss is due to product loss in the equipment (tanks walls, tubing, SMBunit) and when recovering the fractions.

The expected quantity of 5-CN to be recovered was 641.5-g. The totalextract collected was 576.2-g representing a recovery yield of 89.8%.

The product obtained in the extract does not contain detectable amountof 5-Br (see, FIGS. 4 and 5).

Based on these experimental data, the production rate for the separationis 1.31 -kg/d of 5-CN at 17 bars. This corresponds to a productivity of1.49 kg of Citalopram per day per kg of CSP at 17 bars (free of 5-Br).

Let's Discuss Whether or Not to Include the Loading Study as Well as theOther Information in the Discussion Section]

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference for allpurposes.

1. A method for preparing a compound of Formula IV having the followingstructure:

said method comprising: (a) contacting a salt of the compound of FormulaIII having the following structure:

with about 2 to about 10 equivalents of phosphoric acid to form areaction mixture; (b) adding an organic solvent to said reactionmixture; and (c) quenching said reaction mixture with base to form aproduct mixture comprising said compound of Formula IV.
 2. The method ofclaim 1, wherein said salt of the compound of Formula III is a HCl salt.3. The method of claim 1, wherein said phosphoric acid is 20% phosphoricacid.
 4. The method of claim 1, wherein said compound of Formula III iscontacted with about 6 to about 9 equivalents of 20% phosphoric acid. 5.The method of claim 1, wherein said compound of Formula III is contactedwith about 9 equivalents of 20% phosphoric acid.
 6. The method of claim1, wherein said organic solvent in step (b) is a member selected fromthe group consisting of toluene, benzene, xylene, diethylether,t-butylmethylether, dioxane, and mixtures thereof.
 7. The method ofclaim 1, wherein said organic solvent in step (b) is toluene.
 8. Themethod of claim 1, wherein said base is a member selected from the groupconsisting of ammonium hydroxide, sodium hydroxide and potassiumhydroxide.
 9. The method of claim 1, wherein said base is aqueousammonium hydroxide.
 10. The method of claim 1, further comprising: (c)isolating said compound of Formula IV from said product mixture.
 11. Themethod of claim 10, wherein step (c) comprises: (i) separating theorganic phase and the aqueous phase; (ii) re-extracting the aqueousphase with toluene; (iii) combining the organic phases to form acombined organic phase and washing said combined organic phase withwater; and (iv) distilling said washed organic phase to obtain thecompound of Formula IV.
 12. A method for preparing a compound of FormulaV having the following structure:

said method comprising: (a) contacting a compound of Formula IV havingthe following structure:

with a mixture of cuprous cyanide and sodium cyanide to form a reactionmixture; (b) heating said reaction mixture until the reaction iscomplete; and (c) quenching said reaction mixture to form a productmixture comprising said compound of Formula V.
 13. The method of claim12, wherein said compound of Formula IV is in a first organic solvent.14. The method of claim 13, wherein said first organic solvent is amember selected from the group consisting of toluene, benzene, xylene,diethylether, t-butylmethylether, dioxane, and mixtures thereof.
 15. Themethod of claim 14, wherein said first organic solvent is toluene. 16.The method of claim 12, wherein said mixture of cuprous cyanide andsodium cyanide is in a second organic solvent.
 17. The method of claim16, wherein said second organic solvent is a member selected from thegroup consisting of N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidione, quinoline, collidine, xylene, dimethylsulfone,hexamethylphosphoramide and trifluoromethylchlorobenzene.
 18. The methodof claim 16, wherein said second organic solvent isN,N-dimethylformamide.
 19. The method of claim 12, wherein the ratio ofcuprous cyanide:sodium cyanide in said mixture of cuprous cyanide andsodium cyanide is about 2.5:1.0 to about 1:2.5.
 20. The method of claim12, wherein the ratio of cuprous cyanide:sodium cyanide in said mixtureof cuprous cyanide and sodium cyanide is about 0.50:1.0 to about 2.5:1.21. The method of claim 12, wherein the ratio of cuprous cyanide:sodiumcyanide in said mixture of cuprous cyanide and sodium cyanide is about0.75:1.0 to about 1.0:1.0.
 22. The method of claim 13, wherein saidfirst organic solvent is removed from said reaction mixture prior tostep (b).
 23. The method of claim 12, wherein said reaction mixture isquenched with a member selected from the group consisting of aqueoussodium cyanide and aqueous potassium cyanide.
 24. The method of claim20, wherein said reaction mixture is quenched with 10% aqueous sodiumcyanide.
 25. The method of claim 12, further comprising: (d) isolatingsaid compound of Formula V from said product mixture.
 26. The method ofclaim 21, wherein step (d) comprises: (i) adding ethylenediamine and afirst organic solvent to said reaction mixture and separating theorganic phase and the aqueous phase; (ii) re-extracting the aqueousphase with said first organic solvent; (iii) combining the organicphases to form a combined organic phase and back-extracting the combinedorganic phase with an acid to form an acid extract; (iv) neutralizingsaid acid extract with a base to a pH of about 8.5 to about 11 to form aneutralized extract; (v) extracting said neutralized extract with asecond organic solvent to form a second organic solvent extract; (vi)treating said second organic solvent extract with charcoal and removingsaid second organic solvent to generate the compound of Formula V. 27.The method of claim 26, wherein said first and second organic solventsare independently selected from the group consisting of toluene,benzene, xylene, diethylether, t-butylmethylether, dioxane, and mixturesthereof.
 28. The method of claim 27, wherein said first and secondorganic solvents are both toluene.
 29. The method of claim 26, whereinsaid acid in step (iii) is a member selected from the group consistingof HCl, HBr, H₂SO₄, H₃PO₄, trifluoroacetic acid and acetic acid.
 30. Themethod of claim 29, wherein said acid in step (iii) is 20% aqueousacetic acid.
 31. The method of claim 26, wherein said base in step (iv)is a member selected from the group consisting of sodium hydroxide,potassium hydroxide and sodium carbonate.
 32. The method of claim 26,wherein said base in step (iv) is sodium hydroxide.
 33. The method ofclaim 26, wherein in step (iv) said acid extract is neutralized withsaid base to a pH of about 9 to about
 10. 34. The method of claim 26,wherein said compound of Formula V is further purified using simulatedmoving bed chromatography having a stationary phase and a mobile phase.35. The method of claim 34, wherein the stationary phase is a reversephase silica gel and the mobile phase is an organic solvent/watermixture.
 36. The method of claim 35, wherein said reverse phase silicagel is a C₁₈-derivatized silica gel.
 37. The method of claim 35, whereinthe pH of the mobile phase is about 1.5 to about 4.0.
 38. The method ofclaim 37, wherein the pH of the mobile phase is about 2.5.
 39. Themethod of claim 37, wherein the pH of the mobile phase is maintained bythe addition of 0.1 to 2% trifluoroacetic acid.
 40. The method of claim35, wherein said organic solvent in the mobile phase is methanol. 41.The method of claim 35, wherein said organic solvent in the mobile phaseis ethanol.
 42. The method of claim 35, wherein said organic solvent inthe mobile phase is acetonitrile.
 43. The method of claim 34, whereinthe stationary phase is a normal phase silica gel and the mobile phaseis an organic solvent mixture.
 44. The method of claim 42, wherein saidorganic solvent mixture is a mixture of an alcohol, a hydrocarbon and anorganic base.
 45. The method of claim 43, wherein said alcohol is amember selected from the group consisting of methanol, ethanol,n-propanol and isopropanol.
 46. The method of claim 43, wherein saidhydrocarbon is a member selected from the group consisting of heptane,n-heptane, hexane, isohexane, toluene, cyclohexane, benzene andcombinations thereof.
 47. The method of claim 43, wherein said organicbase is a member selected from the group consisting of triethylamine,diethylamine, trimethylamine, dimethylamine, tripropylamine,tributylamine, diisopropylethylamine, dicyclohexylamine anddiethylisopropylamine.
 48. The method of claim 43, wherein said organicbase is present in said organic solvent mixture at about 0.05 to about5%.
 49. The method of claim 48, wherein said organic base is present insaid organic solvent mixture at about 0.1 to about 0.5%.
 50. The methodof claim 48, wherein said organic base is present in said organicsolvent mixture at about 0.2 to about 0.4%.
 51. The method of claim 43,wherein said organic solvent mixture is a mixture of ethanol, heptaneand triethylamine.
 52. The method of claim 34, wherein the stationaryphase is a chiral phase silica gel and the mobile phase is an organicsolvent mixture.
 53. The method of claim 52, wherein said organicsolvent mixture is a mixture of an alcohol, a hydrocarbon and an organicbase.
 54. The method of claim 53, wherein said alcohol is a memberselected from the group consisting of methanol, ethanol, n-propanol andisopropanol.
 55. The method of claim 53, wherein said hydrocarbon is amember selected from the group consisting of heptane, n-heptane, hexane,isohexane, toluene, cyclohexane, benzene and combinations thereof. 56.The method of claim 53, wherein said organic base is a member selectedfrom the group consisting of triethylamine, diethylamine,trimethylamine, dimethylamine, tripropylamine, tributylamine,diisopropylethylamine, dicyclohexylamine and diethylisopropylamine. 57.The method of claim 53, wherein said organic base is present in saidorganic solvent mixture at about 0.05 to about 5%.
 58. The method ofclaim 57, wherein said organic base is present in said organic solventmixture at about 0.1 to about 0.5%.
 59. The method of claim 57, whereinsaid organic base is present in said organic solvent mixture at about0.2 to about 0.4%.
 60. The method of claim 26, wherein said compound ofFormula V is further purified using single column chromatography havinga stationary phase and a mobile phase.
 61. A method for preparing acompound of Formula VI having the following structure:

said method comprising: (a) dissolving a compound of Formula V havingthe following structure:

in an organic solvent to form a reaction mixture; and (b) contactingsaid reaction mixture with HBr to form a product mixture comprising saidcompound of Formula VI.
 62. The method of claim 50, wherein said organicsolvent in step (a) is a member selected from the group consisting ofacetone, methylethylketone, ethylacetate, toluene, benzene, xylene,diethylether, t-butylmethylether, dioxane, and mixtures thereof.
 63. Themethod of claim 51, wherein said organic solvent in step (a) isdiethylether.
 64. The method of claim 51, wherein said organic solventin step (a) is acetone.
 65. The method of claim 51, wherein said HBr isgaseous HBr.
 66. The method of claim 51, wherein said HBr is aqueousHBr.
 67. The method of claim 50, further comprising: (c) isolating saidcompound of Formula VI from said product mixture.
 68. The method ofclaim 50, wherein step (c) comprises: (i) cooling the product mixtureand filtering said product mixture to obtain the compound of Formula VIas a precipitated solid; (ii) washing said precipitated solid with anorganic solvent; and (iii) drying said precipitated solid to obtain thecompound of Formula VI.
 69. The method of claim 55, further comprising(iv) recrystallizing the compound of Formula VI.
 70. The method of claim56, wherein said compound of Formula VI is recrystallized from a solventmixture of toluene and methanol.
 71. The method of claim 56, whereinstep (iv) comprises: (i′) combining said precipitated solid with tolueneand methanol to form a mixture and heating said mixture; (ii′) filteringsaid mixture through Celite and slowly cooling said mixture; (iii′)filtering said mixture to obtain the crystallized solid, washing thecrystallized solid with toluene, and drying said crystallized solid toobtain the compound of Formula VI.
 72. The method of claim 58, whereinin step (ii′) said mixture is cooled to about ambient temperature. 73.The method of claim 58, wherein in step (ii′) said mixture is cooled toabout 0° C. to about 5° C.
 74. The method of claim 56, wherein step (iv)comprises: (i′) combining said precipitated solid with methanol andisopropylalcohol to form a mixture and heating said mixture; (ii′)filtering said mixture through Celite and slowly cooling said mixture;(iii′) filtering said mixture to obtain the crystallized solid, washingthe crystallized solid with isopropylalcohol, and drying saidcrystallized solid to obtain the compound of Formula VI.
 75. A methodfor removing demethyl- and/or didemethyl-impurities from a mixture ofCitalopram containing demethyl- and/or didemethyl impurities in asolvent, said method comprising: (a) contacting said mixture ofCitalopram with a scavenger resin having a functional group that isreactive with a primary or secondary amine to form resin-bound demethyl-and/or didemethyl impurities, wherein said scavenger resin is insolublein said solvent; and (b) filtering said resin-bound demethyl- and/ordidemethyl-impurities, thereby removing said demethyl and/ordidemethyl-impurities from said mixture of Citalopram.
 76. The method ofclaim 75, wherein said functional group is a member selected from thegroup consisting of isocyanates, isothiocyanates, acid chlorides, estersand anhydrides.
 77. The method of claim 75, wherein said scavenger resinis a polystene-based resin.
 78. The method of claim 75, wherein saidscavenger resin is a silica gel-based resin.
 79. The method of claim 77,wherein said polystene-based resin has the following structure:

wherein R is a member selected from the group consisting of isocyanates,isothiocyanates, acid chlorides, esters and anhydrides.